Platelets lacking PIP5KIγ have normal integrin activation but impaired cytoskeletal-membrane integrity and adhesion

Abstract

Key Points Different isoforms of PIP5KIγ fulfill unique functions in platelets.

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

“…S1C) will prevent responding to basal PI(4,5)P 2 levels (average estimates in the cell are 1% of total lipid) but allows a sharp and specific response to highly localized PI(4,5)P 2 production in FAs by PIP5KIγ. On the other hand, Legate et al (34) propose that bulk PI(4,5)P 2 can partially substitute for local PI(4,5)P 2 production, which may explain the differential effects of PIP5KIγ depletion in different cell types (39). We note that lipid involvement in FAK activation fits well with superresolution optical microscopy studies showing that FAK in FAs resides in close proximity to the cell membrane (40).…”

“…However, we note that due to the complexity of FAK signaling, the exact upstream signaling events likely vary in different tissue contexts. In platelets, for example, FAK signaling does not depend on PIPKIγ (39). We note that PI(4,5)P 2 levels are generally not as tightly regulated as, for example, PI(3,4,5)P 3 levels; however, the property of the FAK-PI(4,5)P 2 interaction appears well suited to the characteristics of PI(4,5)P 2 levels in the cell and the localized generation of PI(4,5)P 2 .…”

Selectins and chemokines use shared and distinct signals to activate β2 integrins in neutrophils

“…Platelets lacking PIP5Kg or expressing only PIP5Kg87 still activate b3 integrins, presumably because they also express Rap1b. 33 Platelets lacking both PIP5Kg90 and Rap1b might have more severe defects in activating b3 integrins. Knockdown of PIP5Kg90 in lymphocytes does not prevent chemokine-triggered extension of b2 integrins but does prevent their conversion to the high-affinity conformation.…”

“…33 We perfused bone marrow leukocytes over E-selectin with or without co-immobilized ICAM-1. Neutrophils of both genotypes and their controls exhibited equivalent slow rolling that was blocked by anti-ICAM-1 mAb (Figure 2A,C).…”

A talin mutant that impairs talin-integrin binding in platelets decelerates αIIbβ3 activation without pathological bleeding

“…17 Second, talin is a known binding partner of phosphatidylinositol-4-phosphate 5-kinase g (PIP5KIg) 33 and this complex is speculated to participate in maintaining plasma membrane integrity. 19,34 Importantly, whereas the talin1(L325R) lacks the capacity to activate integrins, it retains the capacity to bind the b3-integrin tail (Figure 4), to bind PIP5KIg, 17 and to mechanically link aIIbb3 to the actin cytoskeleton during clot retraction. 17 Finally, it is possible that talin may participate in integrin outside-in signaling by either promoting integrin clustering and/or acting as an adapter for signaling pathways downstream of integrins such as focal adhesion kinase.…”